Dasatinib



Better Known as: Sprycel

 * Marketed By: Bristol-Myers Squibb
 * Major Indication: Chronic Myelogenous Leukemia (CML)
 * Drug Class: Receptor Tyrosine Kinase (Especially, PDGFR, KIT & BCR-Abl) Inhibitor
 * Date of FDA Approval (Expiration): 2006 (2020)
 * 2009 Global Sales: $421 Million
 * Importance: It is a second generation receptor Tyrosine kinase inhibitor. It binds to Abl with less stringent conformational requirements so it exhibits increased potency compared to Imatinib although with less selectivity. Unlike most RTK inhibitors, Dasatinib binds the active conformation of BCR-Abl. Is used to treat patients with certain Imatinib resistant forms of CML. Controversial due to its nearly $50,000 per year cost.
 * See Pharmaceutical Drugs for more information about other drugs and disorders

Mechanism of Action
Chronic Myelogenous Leukemia (CML) results from a gene defect in a haematological stem cell, producing the kinase, BCR-Abl. Compared to the tightly regulated c-Abl kinase, BCR-Abl has a truncated auto-regulatory domain, leading to constitutive activation of its tyrosine kinase activity. The result of this nearly limitless activation is unregulated phosphorylation of downstream receptors leading to uncontrolled growth and survival of leukemic cells. Like many other receptor tyrosine kinases, BCR-Abl is at an equilibrium between two states, an active state and an auto-regulated inactive state. Dasatinib functions by binding in the ATP site of the active conformation of BCR-Abl. This is unique as Abl inhibitors like Imatinib and Nilotinib bind only the inactive conformation. The well known "DFG triad" is in the "in" conformation in the Dasatinib bound BCR-Abl, with the so-called activation loop extending away from the ATP binding site & P-loop covering the top of the ATP binding site. A critically important residue, Thr 315, is known as the gatekeeper residue, forms a hydrogen with Dasatinib. In other kinases like B-Raf, p38 & KDR, position 315 is occupied by a larger residue that is not conducive to Dasatinib binding, giving Dasatinib its high specificity. A number of point mutations within BCR-Abl result in Imatinib resistance. There are 15 well known Imatinib resistance conferring mutations at positions like 244, 250, 252, 253, 315, 317, 351, and 396. Dasatinib has shown effectiveness with nearly all Imatinib resistant versions of BCR-Abl, with the exception of the T315I/A & T317L/V mutants. In BCR-Abl, Dasatinib is bound by H-bonds to residues Met 318 an Thr 315, along with hydrophobic interactions with residues Ala 380, Leu 370, Met 290, Gly 321, Thr 319, Ala 269, Phe 317, Glu 316, Lys 271, Ile 313, Val 299 & Glu 286, stabilizing the inhibited conformation of the kinase.

To see morphs of the movement of key structural elements Click: DFG Movement, P-Loop Movement , & the Activation Loop Movement.